Development of giant cell arteritis after vaccination against SARS-CoV2: A case report and literature review

Rationale: Giant cell arteritis (GCA) is an autoimmune vasculitis that affects large and medium-sized blood vessels. The mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has been associated with the development of immune-mediated diseases. In this article, we present a case of GCA that developed after vaccination against SARS-CoV2. Patient concerns: A 77-year-old man developed fever, general fatigue, and headache 1 day after the third dose of vaccination against SARS-CoV2. Nodular swelling and tenderness of the bilateral temporal arteries were observed. Diagnoses: Although right temporal artery biopsies were negative, the patient was diagnosed with GCA based on criteria established by the American College of Rheumatology for the classification of GCA. Interventions: The patient received methylprednisolone 1000 mg for 3 days. This was followed by prednisolone 1 mg/kg/d, which was decreased by 10 mg every week to 30 mg. From day 16 of hospitalization, the patient received tocilizumab 162 mg/wk every other week. Outcomes: There was no occurrence of acute side effects. After 38 days of treatment, the condition improved and the patient was discharged from the hospital; as stated above, the dose of prednisolone was tapered to 30 mg/d. Lessons: We experienced a case of GCA that occurred immediately after vaccination against SARS-CoV2 with an mRNA vaccine. Early signs of GCA include fever, fatigue, and headache, and often resemble those noted after vaccination against SARS-CoV2. The potential presence of GCA should be determined in individuals with persistent fever and headache after vaccination against SARS-CoV2.


Introduction
Giant cell arteritis (GCA) is an autoimmune vasculitis of large-and medium-sized blood vessels. It typically occurs in patients aged > 50 years and is mainly characterized by headache, fever, and malaise. [1] In 1990, the American College of Rheumatology established criteria for the classification of GCA. According to this classification, the diagnosis of GCA is reached when at least three of the following 5 criteria are met: age ≥ 50 years at disease onset; new onset of localized headache; temporal artery tenderness or decreased temporal artery pulse; elevated erythrocyte sedimentation rate (Westergren) ≥ 50 mm/h; and biopsy sample including an artery, showing necrotizing arteritis characterized by a predominance of mononuclear cell infiltrates or a granulomatous process with multinucleated giant cells. [1] Although genetic, geographic, and hormonal factors have been implicated, the etiology of GCA is unknown.
The relationships between viral infections, vaccine antigens, and the onset or exacerbation of immune-mediated diseases have been thoroughly investigated. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) causes a fatal infectious disease, that has resulted in a pandemic. The mRNA vaccine was developed as the most important countermeasure against SARS-CoV2 infection, and has exhibited high efficacy in preventing severe disease. Adverse reactions following vaccination The patient and the patient's wife (next of kin) provided written informed consent for the publication of this case report.

Case report
A 77-year-old man with type 2 diabetes mellitus, Basedow's disease, and prostate cancer received 3 doses of an mRNA vaccine against SARS-CoV-2 (BNT162b2; Pfizer-BioNTech, Mainz, Germany). One day later, the patient developed fever, general fatigue, and headache; the symptoms persisted for 3 months. He visited a primary care physician and underwent chest X-ray examination. Following the detection of an abnormality in the chest X-ray examination, the patient was referred to the respiratory department of our hospital.
Physical examination revealed a body temperature of 38.0°C, blood pressure of 103/72 mm Hg, and pulse rate of 65 beats/min. Auscultation confirmed that his lungs were clear, abdominal examination was unremarkable without hepatosplenomegaly, and neurological examination yielded normal findings. Nodular swelling and tenderness of the bilateral temporal arteries ( Fig. 1A and B), as well as tenderness of the bilateral femoral muscles, were observed. Chest X-ray examination and computed tomography demonstrated slight shadows suggestive of chronic lower respiratory tract infection. Nevertheless, these findings could not explain the cause of symptoms in this patient. Contrast-enhanced computed tomography did not reveal evidence of vasculitis. Laboratory examinations demonstrated elevations in the serum levels of C-reactive protein (13.4 mg/dL), white blood cell count (13.2 × 10 9 /L), and erythrocyte sedimentation rate (62 mm/h). In contrast, the serum levels of creatine kinase, concentration of thyroid hormones, and urinary findings were normal. Antibodies against extractable nuclear antigens, rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and anti-neutrophil cytoplasmic antibodies were not detected. Analysis using polymerase chain reaction for SARS-CoV2 yielded negative results. Further analyses for serum antibodies against the SARS-CoV2 core protein and spike protein were negative and positive, respectively. These results indicated the absence of previous infection with SARS-CoV2.
Consequently, GCA was suspected, and the patient was admitted to our hospital for diagnosis and treatment. Ultrasound  echography revealed a halo sign surrounding the bilateral temporal arteries (Fig. 1C and D). There was no obvious evidence of vasculitis (i.e., inflammatory cells and giant cells) in right temporal artery tissue collected on day 3 of hospitalization (Fig. 2). According to the criteria established by the American College of Rheumatology, the patient was diagnosed with GCA. [1] As shown in Figure 3, he received treatment with methylprednisolone 1000 mg/d on day 4 of hospitalization, and prednisolone 1 mg/kg/d on day 7 of hospitalization. Following treatment, the fever resolved and the headache improved. On day 16 of hospitalization, the patient received tocilizumab 162 mg/wk through subcutaneous injection. There was no recurrence of headache or fever. On day 42 of hospitalization, the dose of prednisolone was tapered to 30 mg/d. Eventually, the patient was discharged from the hospital on day 45.

Discussion
We reported a case of GCA that occurred immediately after vaccination against SARS-CoV2 with an mRNA vaccine.
Several reports have proposed a link between vaccination against SARS-CoV2 with an mRNA vaccine and the development of GCA (Table 1). [4][5][6][7][8] Six patients developed GCA after vaccination against SARS-CoV2; of those, 2 and 4 patients had received the viral vector vaccine and the mRNA vaccine, respectively. The onset time did not depend on the number of vaccinations, and all cases of GCA developed within 10 days after vaccination. The patients were treated with glucocorticoids (all patients), tocilizumab (1 patient), and methotrexate (1 patient), and responded well to the therapy. The present case was similar to previous reports; GCA occurred 1 day after the vaccination, and the patient responded well to treatment. The pathological analysis of our case was negative; however, the diagnosis of GCA was based on the criteria established by the American College of Rheumatology. Previous reports have shown both pathologically positive and negative cases of GCA; 2 of the 6 patients had a positive temporal biopsy, whereas the remaining 4 patients had a negative temporal biopsy or not described. The frequency of positive pathological findings for GCA that developed after  Table 1 Clinical characteristics of 6 cases of giant cell arteritis after vaccination against severe acute respiratory syndrome coronavirus 2.
Cadiou et al [6] Cadiou et al [6] Anzola et al [5] Greb et al [4] Xia et al [8] Ishizuka et al [7] Present case vaccination against SARS-CoV2 is lower than that noted for conventional GCA (the sensitivity of temporal artery biopsy in conventional GCA is 92.9%). [1] The function of mRNA vaccines is based on the following steps: translation of mRNA encoding the viral antigen by intracellular ribosomes; production of the spike protein; presentation of the spike protein as antigen on the cell surface by the major histocompatibility complex; and production of antibodies against the target virus. [9] Studies have investigated the mechanism by which mRNA vaccines induce GCA; the onset of this condition is attributed to cross-reaction of produced antibodies with tissues. [6] In addition, conventional GCA, SARS-CoV2 infection, and adverse reactions after vaccination against SARS-CoV2 promote excessive production of interleukin-6, which may be involved in the pathogenesis. [6] Therefore, the use of an mRNA vaccine against SARS-CoV2 may be linked to the development of GCA.
The present case differs from cases of typical GCA in terms of the negative pathological analysis. Except for pathology, the diagnosis of CGA in previously reported cases that developed after vaccination against SARS-CoV2 was mainly based on a combination of imaging, laboratory testing, and clinical symptom recording. Therefore, GCA that develops after vaccination against SARS-CoV2 may differ from the original one, such as "GCA-like vaccine adverse reaction." As mentioned above, there are similarities between the adverse reactions associated with mRNA vaccines and symptoms of GCA (e.g., fever, headache, fatigue). Therefore, additional cases should be evaluated to elucidate the pathogenesis of GCA that develops after vaccination against SARS-CoV2.